POS0639 PHARMACOKINETIC BOOSTING TO ENABLE A ONCE-DAILY REDUCED DOSE OF TOFACITINIB IN PATIENTS WITH RHEUMATOID ARTHRITIS AND PSORIATIC ARTHRITIS
Authors: C. Van der Togt, L. M. Verhoef, B. Van den Bemt, N. Den Broeder, R. Ter Heine, A. Den Broeder
Journal: Annals of the Rheumatic Diseases (2022)

Background Tofacitinib is an effective drug for rheumatoid arthritis (RA) and psoriatic arthritis (PsA). As tofacitinib is metabolized by the CYP3A4-enzyme, the manufacturer recommends to reduce the dose with 50% when combined with CYP3A4-inhibitors. This creates an opportunity to improve cost-effectiveness and patient experience by deliberately combining tofacitinib 5 mg once daily with a registered CYP3A4-inhibitor, cobicistat. Objectives Primary: pharmacokinetic (PK) bioequivalence of tofacitinib 5 mg and cobicistat 150 mg once daily (intervention) to tofacitinib 5 mg twice daily (control). Secondary: clinical efficacy (DAS28-CRP), safety, patient preference, and predictive modelling of long-term DAS28 and ACR20 response. Methods This open-label, cross-over, monocentre study (Sint Maartenskliniek, The Netherlands) included patients with RA or PsA, using tofacitinib 5mg twice daily for ≥ 14 days without co-medication affected by CYP3A4-inhibition. At the first sampling day, plasma samples of tofacitinib were collected pre-dose and 0.5, 1, 2, 3, 4, 6, 9 and 12 hours post-dose. Subsequently, patients switched treatment to tofacitinib 5 mg and cobicistat 150 mg once daily, and 2-6 weeks thereafter, another PK sampling was performed at the same timepoints and additionally at 24 hours post-dose. PK bioequivalence was defined as the 90% confidence interval of the average tofacitinib concentration (C avg,ss ) geometric mean ratio (GMR) falling between 80-125%. Secondary endpoints included efficacy (change in mean DAS28-CRP between sampling days), safety, and patient preference (7-point Likert scale at study end). Additionally, differences between both regimens in DAS28 and probability of ACR20 response were predicted using a validated PK/PD model.[1] Results Between September 2019 and March 2021, 27 participants were included. Twenty-five participants completed both PK measurements and were included in the primary analysis. The C avg,ss GMR was 84.8%, 90% CI 75.1% to 95.6%. The difference in absolute DAS28-CRP was 0.05 (95% CI -0.50 to 0.59, intervention to control). There were no significant or relevant differences in adverse events between both regimens. Patient preference was 56% for intervention (Likert score 5-7), versus 18% for control (score 1-3). Median differences in predicted DAS28 and probability of ACR20 response were 0.03 (95% CI -0.16 to 0.22; intervention-control) and -0.01 (-0.07 to 0.05), respectively. Conclusion Due to slightly lower tofacitinib concentrations during combination therapy, pharmacokinetic bioequivalence could not formally be established. However, because of comparable short-term clinical efficacy and safety, a clear patient preference and no relevant differences in predicted DAS28 and ACR20-response at maximum efficacy, pharmacokinetic boosting seems an attractive strategy to improve cost-effectiveness of tofacitinib treatment. References [1]Lamba M, et al. Clin Pharmacol Ther. 2017 Jun;101(6):745-753. Table 1. Baseline characteristics Participants (n=27) Age (years) 57 ± 11 Female gender 15 (56%) Weight (kg) 85 ± 21 GFR calculated by CKD-epi (ml/min/1.73m 2 ) 80 ± 14 Disease • RA 17 (63%) • RF and/or ACPA positive (RA only) 14 (82%) • PsA 10 (37%) Disease duration (years) 11 (4-18) Tofacitinib use ≤ 3 months 22 (81%) DAS28-CRP at baseline 3.27 ± 1.41 Concomitant csDMARD use 8 (30%) • methotrexate 4 (15%) • leflunomide 4 (15%) Previous b/tsDMARDs (n) 3 (2-4) Either displayed as number (%), mean ± standard deviation or median (interquartile range). Percentages were calculated over the total number of participants unless indicated otherwise. Figure 1. Visual representation of measured bioequivalence (A), and predicted difference in DAS28 response (B) and probability of ACR response (C) A: GMR (diamond) with 90% CI; vertical dotted lines: equivalence margin (80-125%). B/C: median predicted value (diamond) with 95% CI; vertical dotted line: post-hoc noninferiority margins (+ 0.6 for DAS28 and -10% for ACR20). Acknowledgements We thank the Radboud Technology Centre for Clinical Trials and Kasper Jolink for performing blood sampling for this study, and the Radboudumc Clinical Pharmacy for the tofacitinib serum level analysis. Disclosure of Interests Celeste van der Togt: None declared, L.M. Verhoef: None declared, Bart van den Bemt Speakers bureau: UCB, Pfizer, Sanofi-Aventis, Galapagos, Amgen en Eli Lilly, Nathan den Broeder: None declared, Rob ter Heine: None declared, Alfons den Broeder Grant/research support from: Abbvie, Galapagos, Pfizer, Novartis, Lilly, Sanofi, Gilead